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Marybeth A. Pysz

Bio: Marybeth A. Pysz is an academic researcher from Stanford University. The author has contributed to research in topics: Cancer & Cyclin D1. The author has an hindex of 25, co-authored 40 publications receiving 2367 citations. Previous affiliations of Marybeth A. Pysz include North Carolina State University & University of California, San Francisco.

Papers
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Journal ArticleDOI
TL;DR: Current preclinical findings and advances in instrumentation suggest that these molecular imaging methods have numerous potential clinical applications and will be translated into clinical use in the near future.

487 citations

Journal ArticleDOI
TL;DR: The authors targeted DLL3 with an antibody conjugated to a cytotoxic drug, which proved to be much more effective than standard chemotherapy for treating patient-derived tumor xenografts and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.
Abstract: The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.

434 citations

Journal ArticleDOI
TL;DR: Human MB(KDR) allow in vivo imaging and longitudinal monitoring of VEGFR2 expression in human colon cancer xenografts and in vivo receptor blocking with anti-VEGFR2 antibody is tested.
Abstract: Clinically translatable human kinase insert domain receptor–targeted contrast microbubbles can be designed and successfully used for in vivo molecular US of vascular endothelial growth factor receptor 2 in the tumor vasculature in mice.

166 citations

Journal ArticleDOI
TL;DR: The authors demonstrated the effectiveness of this therapy in mouse models of several tumor types and confirmed that it reduces tumor-initiating cells and outperforms standard chemotherapy, and also had some unexpected benefits, reducing tumor angiogenesis and promoting antitumor immunity.
Abstract: Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non-small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient-derived xenografts (PDXs). To deliver a potent anticancer drug to PTK7-expressing TICs, we generated a targeted antibody-drug conjugate (ADC) composed of a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline-based linker, and Aur0101, an auristatin microtubule inhibitor. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of TICs, as determined by serial transplantation experiments. In addition to reducing the TIC frequency, the PTK7-targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells. Together, these preclinical data demonstrate the potential for the PTK7-targeted ADC to improve the long-term survival of cancer patients.

112 citations

Journal ArticleDOI
TL;DR: Two open reading frames (chiA and chiB) were identified in the genome of P. furiosus, which encodes chitinases with sequence similarity to proteins from the glycosyl hydrolase family 18 in less-thermophilic organisms, indicating that these two enzymes work together to recruit chit in-based substrates for P.furiosus growth.
Abstract: Pyrococcus furiosus was found to grow on chitin, adding this polysacharide to the inventory of carbohydrates utilized by this hyperthermophilic archaeon. Accordingly, two open reading frames (chiA [Pf1234] and chiB [Pf1233]) were identified in the genome of P. furiosus, which encodes chitinases with sequence similarity to proteins from the glycosyl hydrolase family 18 in less-thermophilic organisms. Both enzymes contain multiple domains that consist of at least one binding domain and one catalytic domain. ChiA (ca. 39 kDa) contains a putative signal peptide, as well as a binding domain (ChiABD), that is related to binding domains associated with several previously studied bacterial chitinases. chiB, separated by 37 nucleotides from chiA and in the same orientation, encodes a polypeptide with two different proline-threonine-rich linker regions (6 and 3 kDa) flanking a chitin-binding domain (ChiBBD [11 kDa]), followed by a catalytic domain (ChiBcat [35 kDa]). No apparent signal peptide is encoded within chiB. The two chitinases share little sequence homology to each other, except in the catalytic region, where both have the catalytic glutamic acid residue that is conserved in all family 18 bacterial chitinases. The genes encoding ChiA, without its signal peptide, and ChiB were cloned and expressed in Escherichia coli. ChiA exhibited no detectable activity toward chitooligomers smaller than chitotetraose, indicating that the enzyme is an endochitinase. Kinetic studies showed that ChiB followed Michaelis-Menten kinetics toward chitotriose, although substrate inhibition was observed for larger chitooligomers. Hydrolysis patterns on chitooligosaccharides indicated that ChiB is a chitobiosidase, processively cleaving off chitobiose from the nonreducing end of chitin or other chitooligomers. Synergistic activity was noted for the two chitinases on colloidal chitin, indicating that these two enzymes work together to recruit chitin-based substrates for P. furiosus growth. This was supported by the observed growth on chitin as the sole carbohydrate source in sulfur-free media.

96 citations


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Journal ArticleDOI
TL;DR: New developments in the cancer stem cell field are discussed in relationship to changing insights into how normal stem cells maintain healthy tissues and the first successes of therapies based on the CSC concept are emerging.
Abstract: The cancer stem cell (CSC) concept was proposed four decades ago, and states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It has gradually become clear that many tumors harbor CSCs in dedicated niches, and yet their identification and eradication has not been as obvious as was initially hoped. Recently developed lineage-tracing and cell-ablation strategies have provided insights into CSC plasticity, quiescence, renewal, and therapeutic response. Here we discuss new developments in the CSC field in relationship to changing insights into how normal stem cells maintain healthy tissues. Expectations in the field have become more realistic, and now, the first successes of therapies based on the CSC concept are emerging.

1,686 citations

Journal ArticleDOI
TL;DR: Strategies to select the best target antigens as well as suitable cytotoxic drugs; the design of optimized linkers; the discovery of bioorthogonal conjugation chemistries; and toxicity issues are discussed.
Abstract: Antibody-drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab emtansine (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody. Furthermore, lessons learned during the past decade are now being used in the development of third-generation ADCs. In this Review, we discuss strategies to select the best target antigens as well as suitable cytotoxic drugs; the design of optimized linkers; the discovery of bioorthogonal conjugation chemistries; and toxicity issues. The selection and engineering of antibodies for site-specific drug conjugation, which will result in higher homogeneity and increased stability, as well as the quest for new conjugation chemistries and mechanisms of action, are priorities in ADC research.

1,363 citations

Journal ArticleDOI
TL;DR: It is believed these newly developed multifunctional NIR dyes will broaden current concept of tumor targeted imaging and hold promise to make an important contribution to the diagnosis and therapeutics for the treatment of cancer.

1,235 citations

Journal ArticleDOI
08 Aug 2008-Cell
TL;DR: Sestrin1 and Sestrin2 provide an important link between genotoxic stress, p53 and the mTOR signaling pathway and are demonstrated to activate the AMP-responsive protein kinase (AMPK) and target it to phosphorylate TSC2 and stimulate its GAP activity, thereby inhibiting mTOR.

1,126 citations

Journal ArticleDOI
TL;DR: This manuscript offers a more comprehensive overview of the primary functions of each component of the TME in cancer initiation, progression, and invasion and includes primary therapeutic targeting markers for each player.
Abstract: Tumorigenesis is a complex and dynamic process, consisting of three stages: initiation, progression, and metastasis. Tumors are encircled by extracellular matrix (ECM) and stromal cells, and the physiological state of the tumor microenvironment (TME) is closely connected to every step of tumorigenesis. Evidence suggests that the vital components of the TME are fibroblasts and myofibroblasts, neuroendocrine cells, adipose cells, immune and inflammatory cells, the blood and lymphatic vascular networks, and ECM. This manuscript, based on the current studies of the TME, offers a more comprehensive overview of the primary functions of each component of the TME in cancer initiation, progression, and invasion. The manuscript also includes primary therapeutic targeting markers for each player, which may be helpful in treating tumors.

964 citations